1. Field of the Invention
The present invention relates to compositions and methods for achieving the efficient allylic oxidation of organic molecules, especially olefins and steroids, under aqueous conditions. The invention concerns the use of dirhodium (II,II) “paddlewheel complexes, and in particular, dirhodium carboximate as catalyst and tert-butyl hydroperoxide as oxidant for the reaction. The use of aqueous conditions is particularly advantageous in the allylic oxidation of delta-4 and delta-5 steroids, which could not be effectively oxidized using anhydrous methods, and in extending allylic oxidation to enamides and enol ethers.
2. Description of Related Art
Allylic oxidation holds a venerable position in organic synthesis. The regioselective functionalization of an allylic C—H bond with oxygen is a value-added operation yielding a wide range of synthetically useful products, including the direct synthesis of enones and enediones from the oxidation of readily available alkenes (Catino, A. J. et al. (2004) “Dirhodium (II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623).
Non-catalytic methods for achieving allylic oxidation have been disclosed (e.g., methods employing stoichiometric chromic acid derivatives and selenium dioxide) (see e.g., U.S. Pat. No. 6,384,251; Arigoni, D. et al. (1973) J. Am. Chem. Soc. 95(23):7917-7919; Umbreit, M. A. et al. (197) “Allylic Oxidation Of Olefins By Catalytic And Stoichiometric Selenium Dioxide With tert-Butyl Hydroperoxide,” J. Am. Chem. Soc. 99:5526-5528; Rapoport, H. et al. (1971) J. Am. Chem. Soc. 93(19):4835-4840; Stephenson, L. M. et al. (1979) J. Org. Chem. 44(25):4683-4689; Pearson, A. J. et al. Tetrahedron Lett. (1984) 25:1235; Rabjohn, N. (1976) “Selenium Dioxide Oxidation,” Org. React. 24:261-415; Crich, D. et al. (2004) “Catalytic Allylic Oxidation with a Recyclable, Fluorous Seleninic Acid,” Org. Lett. 6:775-777; Zeni, G. et al. (2003) “A Convenient Preparation Of Chalcogenoenynes From β-Bromovinyl Ketene Chalcogenoacetals,” Synlett 12:1880-1882; Shing, T. M. K. et al. (2005) “Total Synthesis Of (−)-Samaderine Y From (S)-(+)-Carvone,” Angew. Chem. Int. Ed. 44:7981-7984; Hua, Z. et al. (2005) “The Synthesis and Preliminary Biological Evaluation of a Novel Steroid with Neurotrophic Activity: NGA0187,” J. Org. Chem. 70:9849-9856; Salmond, W. G. et al. (1978) “Allylic Oxidation With 3,5-Dimethylpyrazole. Chromium Trioxide. Complex Steroidal .DELTA.5-7-Ketones,” J. Org. Chem. 43:2057-2059).
However, the selective oxidative functionalization of allylic, benzylic and steroidal hydrocarbons using transition metal catalysis has been a long-standing goal in organic process development (Catino, A. J. et al. (2005) Org. Lett., 7(23):5167-5170). Because of the stabilization offered to reaction intermediates, allylic and benzylic oxidations have been preferred targets, and peroxide-based oxidants (and in particular, tert-butyl hydroperoxide (“TBHP”) have been the reagents of choice (Catino, A. J. et al. (2005) Org. Lett., 7(23):5167-5170; Bulman Page, P. C.; McCarthy, T. J. In COMPREHENSIVE ORGANIC SYNTHESIS; Trost, B. M., Ed.; Pergamon: Oxford, UK, 1991; Vol. 7, p 83; Olah, G. A.; Molnár, Á. Oxidation-Oxygenation. In HYDROCARBON CHEMISTRY, 2nd ed; Wiley: Hoboken; 2003; p 427.
In particular, such oxidative functionalizations have been achieved using TBHP in conjunction with the transition-metal catalyst, dirhodium(II,III) tetrakis(caprolactamate) (“Rh2(cap)4”) (Catino, A. J. et al. (2005) Org. Lett. 7:2787; Catino, A. J. et al. (2006) J. Amer. Chem. Soc. 128:5648-5649; Catino, A. J. et al. (2004) “Dirhodium(II) Caprolactamate: An Exceptional Catalyst for Allylic Oxidation,” J. Am. Chem. Soc. 126:13622-13623; Catino, A. J. et al. (2005) Org. Lett., 7(23):5167-5170).
Reaction rates are slow (requiring multiple hours to come to completion), and yields have been found to be heavily dependent on the employed solvents, with the reaction yield increasing with decreasing solvent polarity (Miller, R. A. et al. (1996) “A Ruthenium Catalyzed Oxidation Of Steroidal Alkenes To Enones,” Tetrahedron Lett. 37:3429-3432). Suitable solvents have included 1,2 dichloroethane (“DCE”) and dichloromethane (Catino, A. J. et al. (2005) Org. Lett., 7(23):5167-5170). Inorganic base (and in particular, (NH4)2CO3, NaHCO3 or (NH4)OAc has been shown to enhance reaction yield (Catino, A. J. et al. (2005) Org. Lett., 7(23):5167-5170). Miller, R. A. et al. (1996) reported the use of an aqueous preparation of TBHP (“T-HYDRO®,” 70% TBHP in water; Aldrich Chemical Company) and ruthenium trichloride to achieve the oxidation of steroidal alkenes to enones (Miller, R. A. et al. (1996) “A Ruthenium Catalyzed Oxidation Of Steroidal Alkenes To Enones,” Tetrahedron Lett. 37:3429-3432). Shultz et al. disclosed the use of pyridinium dichromate and TBHP to catalyze the oxidation of olefin (Schultz, A. G. et al. J. Org. Chem. (1998) 63:7795). This procedure has been applied to the oxidation of Δ5-steroids (Fousteris, M. A. et al. (2006) “Improved Chromium-Catalyzed Allylic Oxidation Of Δ5-Steroids With T-Butyl Hydroperoxide,” J. Mol. Catal. A: Chem. 250:70-74). Corey et al. described a catalytic allylic oxidation for the conversion of α,β-enones into 1,4-enediones using palladium-catalysis (Yu, J.-Q. et al. (2003) “A Mild, Catalytic, and Highly Selective Method for the Oxidation of α,β-Enones to 1,4-Enediones, J. Am. Chem. Soc. 125:3232-3233; Yu, J.-Q. et al. (2002) “Diverse Pathways for the Palladium(II)-Mediated Oxidation of Olefins by tert-Butylhydroperoxide,” Org. Lett. 4:2727-2730; Yu, J.-Q. et al. (2005) “Pd(OH)2/C-Mediated Selective Oxidation of Silyl Enol Ethers by tert-Butylhydroperoxide, a Useful Method for the Conversion of Ketones to α,β-Enones or β-Silyloxy-α,β-enones,” Org. Lett. 7:1415-1417).
Mechanistically, it was proposed that oxidation proceeds through an unusual Pd2+/Pd1+ catalytic cycle. Treatment of PdII(OH)2 with TBHP generates PdII(OOtBu)2 which homolytically dissociates to form PdI(OOtBu) and tert-butyl peroxy radical. Hydrogen atom abstraction generates a carbon-centered radical.
Applications in natural product synthesis using palladium-catalyzed allylic oxidation have recently appeared due to the ease of using commercial Pd(OH)2/C, mild reaction conditions, and selectivity. For example, a palladium-catalyzed allylic oxidation was used in the synthesis of the hydroazulene of guanacastepene A, a diterpenoid that exhibits potency against methicillin-resistant and vancomycin-resistant pathogens (Chiu, P. et al. Org. Lett (2004) 6:613). Using slightly modified conditions, hydroazulene has been oxidized in 65% yield over 48 hours at 40° C. (see, Magnus, P. et al. Org. Lett. (2005) 7:3853; Manzano, F. L. et al. Org. Lett. (2006) 8:2879). Recently, Shing, T. K. M. et al. described a metal-catalyzed allylic oxidation of a cyclic olefin (Shing, T. M. K. et al. (2005) “Total Synthesis Of (−)-Samaderine Y From (S)-(+)-Carvone,” Angew. Chem. Int. Ed. 44:7981-7984). Shing and coworkers further reported the allylic oxidation of a wide range of substrates catalyzed by manganese(III) acetate (Mn(OAc)3.2H2O) in conjunction with anhydrous TBHP (Shing, T. K. M. et al. (2006) “Mild Manganese(III) Acetate Catalyzed Allylic Oxidation: Application to Simple and Complex Alkenes,” Org. Lett. 8:3149-3151). The reaction was particularly amenable to allylic oxidation of Δ5-steroids to Δ5-en-7-ones. Molecular sieves were required to remove deleterious water that was shown to cause catalyst destruction. The manganese-catalyzed allylic oxidation was also extended to simple cyclic alkenes. The reactions were both chemo- and regio-selective across a broad range of substrates.
The oxidative MANNICH REACTION involves the direct catalytic C—H oxidation of a tertiary amine followed by nucleophilic capture. In light of the ability of Rh2(cap)4 to mediate allylic and benzylic oxidation in conjunction with TBHP, the ability of these reagents to mediate the MANNICH REACTION was assessed by Catino, A. J. et al. (2006) and found to be capable of mediating a MANNICH REACTION with N,N-dimethylaniline (Catino, A. J. et al. (2006) J. Amer. Chem. Soc. 128:5648-5649). Catino, A. J. et al. (2006) reported that since iminium ions (the MANNICH REACTION intermediate) were known to be stabilized by polar solvents, an aqueous preparation of TBHP (“T-HYDRO®,” 70% TBHP in water) was employed. (Catino, A. J. et al. (2006) J. Amer. Chem. Soc. 128:5648-5649).
Despite all such advances, a need remains for improved methods of allylic oxidation, particularly methods capable of oxidizing alkenes at their allylic position to unsaturated carbonyl compounds (or arenes at their benzyllic position) when these reactions are catalyzed under aqueous conditions. Of particular importance are such methods that would be applicable to sterols, terpenes and unsaturated fatty acids, which are not oxidized by prior procedures that employ non-aqueous media. The present invention is directed to this and other goals.